MTARC1 and HSD17B13 Variants Have Protective Effects on Non-Alcoholic Fatty Liver Disease in Patients Undergoing Bariatric Surgery

Abstract

The severity of hepatic steatosis is modulated by genetic variants, such as patatin-like phospholipase domain containing 3 (PNPLA3) rs738409, transmembrane 6 superfamily member 2 (TM6SF2) rs58542926, and membrane-bound O-acyltransferase domain containing 7 (MBOAT7) rs641738. Recently, mitochondrial amidoxime reducing component 1 (MTARC1) rs2642438 and hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) rs72613567 polymorphisms were shown to have protective effects on liver diseases. Here, we evaluate these variants in patients undergoing bariatric surgery. A total of 165 patients who underwent laparoscopic sleeve gastrectomy and intraoperative liver biopsies and 314 controls were prospectively recruited. Genotyping was performed using TaqMan assays. Overall, 70.3% of operated patients presented with hepatic steatosis. NASH (non-alcoholic steatohepatitis) was detected in 28.5% of patients; none had cirrhosis. The increment of liver fibrosis stage was associated with decreasing frequency of the MTARC1 minor allele (p = 0.03). In multivariate analysis MTARC1 was an independent protective factor against fibrosis ≥ 1b (OR = 0.52, p = 0.03) and ≥ 1c (OR = 0.51, p = 0.04). The PNPLA3 risk allele was associated with increased hepatic steatosis, fibrosis, and NASH (OR = 2.22, p = 0.04). The HSD17B13 polymorphism was protective against liver injury as reflected by lower AST (p = 0.04) and ALT (p = 0.03) activities. The TM6SF2 polymorphism was associated with increased ALT (p = 0.04). In conclusion, hepatic steatosis is common among patients scheduled for bariatric surgery, but the MTARC1 and HSD17B13 polymorphisms lower liver injury in these individuals.

Divergent role of Mitochondrial Amidoxime Reducing Component 1 (MARC1) in human and mouse

“…In this study we used exome-wide association analysis in over 500,000 individuals to identify several novel rare pLOFs variants in MARC1 with phenotypes similar to previously reported p.Ala165Thr (A165T) and p.Met187Lys (M187K) variants [11][12][13][14][15][16][17][18][19]. We showed p. A165T substitution in MARC1 causes protein instability, leading to the lower MARC1 protein levels in the livers of human carriers of MARC1 p.A165T variant, confirming this variant is a loss of function.…”

“…These studies revealed several missense variants that are associated with lipid accumulation and NAFLD progression [3][4][5][6][7][8][9][10]. Recent genome-wide association studies discovered that common MARC1 missense variants (p. A165T, rs2642438 G>A and p.M187K, rs17850677 T>A) and several rare MARC1 putative loss of function (pLOF) variants (p.R200Ter, p.R305Ter) in humans are associated with decreased liver fat, lower blood ALT, lower alkaline phosphatase, reduced LDL and total cholesterol, as well as protection from all-cause of liver cirrhosis [11][12][13][14][15][16][17][18][19]. MARC1 (mitochondrial amidoxime-reducing component 1, known also as MOSC1 and MTARC1) is a molybdenum containing enzyme anchored on the outer mitochondria membrane.…”

mARC1 in MASLD: Modulation of lipid accumulation in human hepatocytes and adipocytes

“…Several human genes with potential causal relationships to MASH phenotypes have been discovered through population genetics approaches, including the mitochondrial amidoxime–reducing component 1 gene ( MTARC1 , encoding outer mitochondrial membrane protein mARC1). 8 9 10 11 12 13 Missense and nonsense variants in MTARC1 were identified in a genome-wide association study (GWAS), which implicated these variants in protecting their carriers from MASH phenotypes, including reduced risk for MASH, hepatic steatosis, liver enzyme elevations, cirrhosis, and all-cause liver-related mortality. 9 12 …”

“… 8 9 10 11 12 13 Missense and nonsense variants in MTARC1 were identified in a genome-wide association study (GWAS), which implicated these variants in protecting their carriers from MASH phenotypes, including reduced risk for MASH, hepatic steatosis, liver enzyme elevations, cirrhosis, and all-cause liver-related mortality. 9 12 …”

Molecular Mechanism of Chronic Viral and Non-Viral Liver Diseases

“…Hepatic steatosis is common among patients scheduled for bariatric surgery, and steatohepatitis and liver fibrosis have been reported as potential complications of traditional jejunoileal bypass surgery [ 14 ]. Kalinowski et al also reported that mitochondrial amidoxime reducing component 1 (MTARC1) rs2642438 and hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) rs72613567 polymorphisms had protective effects on nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) [ 15 ], although functions of these gene-coding proteins should be further explored.…”